Are you using all of the resources in your armamentarium to save your patients’ sight? Don’t miss this recap of how our experts, Dr. Avni Finn and Dr. Jay Sridhar, are translating the latest data into practice with early referral and timely treatment of diabetic retinopathy.
New Perspectives on Managing Diabetic Retinopathy
Risk of Blindness at Initial Diagnosis
Ophthalmologists know that diabetic retinopathy (DR) can present in any of the 34 million patients with diabetes in the United States and that the risk of DR increases with a higher hemoglobin A1c (HbA1c) and longer disease duration. This raises the question: What is a patient’s risk of blindness at their initial diagnosis of DR? A 2021 retrospective study by Wykoff et al. provides answers to this question through its analysis of data from the American Academy of Ophthalmology’s Intelligent Research in Sight (IRIS) Registry on the risk of blindness in patients newly diagnosed with DR.1 The study demonstrated that patients newly diagnosed with moderate or severe nonproliferative DR (NPDR) or with proliferative DR (PDR) had 2.6, 3.6, and 4.0 times greater risk, respectively, of sustained blindness at 2 years than patients newly diagnosed with mild NPDR (Figure 1).1 These findings indicate that the risk of sustained blindness increases as patients progress from moderate NPDR to PDR,1 underscoring the importance of early diagnosis, close follow-up, and effective patient education.
Figure 1. Risk of blindness with DR.1
Clinical Staging of DR
Staging of DR is necessary because management is based on the severity level. In clinical studies, the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS) is commonly used to assess the severity of DR (Figure 2). However, its complex numbering system makes it less useful clinically. The DR Disease Severity Scale of the American Academy of Ophthalmology (AAO) is more widely used in clinical practice, and its familiar “4-2-1” rule is the basis for diagnosing severe NPDR (Figure 2). Review this animation to visualize the various stages of NPDR. Importantly, ophthalmologists need to be especially aware of the need to carefully evaluate not only the posterior pole but also the periphery of the retina.
Figure 2. Grading scales for DR.
Case Study 1: Ultra-Widefield FA
A 37-year-old woman had a complaint of “new spots” OS. She had a medical history of well-controlled type 1 diabetes for >20 years. Wide-field fundus imaging showed some dot-blot hemorrhages and microaneurysms in the temporal and inferior peripheral quadrants OD (Figure 3). Notably, wide-field fluorescein angiography (FA) showed retinal nonperfusion, capillary drop-out, and multiple areas of neovascularization with leakage throughout her retina OD, all of which were not apparent on fundus imaging (Figure 3).
Figure 3. Patient’s ultra-widefield fundus (top) and FA (bottom) imaging showing DR pathology OD.
This case highlights the importance of obtaining wide-field imaging and FA in patients with DR, especially those with an advanced stage of disease. However, ophthalmologists should also consider these diagnostic tools in patients with moderate DR. The reasons for this are 1) the severity of retinopathy is often underestimated, as seen in this patient case, and 2) treatment options have expanded owing to recent clinical trial data.
Pivotal Studies: Protocol W and PANORAMA
Protocol W and PANORAMA, both 2021 randomized clinical trials, demonstrated that early treatment with anti-vascular endothelial growth factor (anti-VEGF) in eyes with moderate to severe NPDR without diabetic macular edema (DME) reduced the risk of vision-threatening complications (VTCs).2,3 Protocol W was a prospective study that enrolled 328 adults (399 eyes) with moderate to severe NPDR without center-involved DME (CI-DME).2 At baseline, 1, 2, and 4 months, then every 4 months through 2 years, eyes randomly received injections of 2.0 mg of aflibercept or sham.2 The primary outcome was the development of CI-DME with vision loss or PDR through 2 years.2 Eyes treated with aflibercept had a threefold reduced risk of CI-DME (4.1% aflibercept vs 14.8% sham) and twofold reduced risk of PDR (13.5% aflibercept vs 33.2% sham) compared with sham (Figure 4).2
Figure 4. Anti-VEGF therapy reduced the risk of PDR or CI-DME in moderate to severe NPDR in the Protocol W study.2 y, year.
PANORAMA, a phase 3 double-blind study, analyzed the risk of VTCs and CI-DME in eyes receiving anti-VEGF therapy with moderately severe and severe NPDR without DME and with a best corrected visual acuity (BCVA) of 20/40 or better.3 The 402 adults (402 eyes) in the study received intravitreal injections for up to 100 weeks as 1) 2.0 mg of aflibercept either every 16 weeks after 3 initial monthly doses and one 8-week interval (Q16W) or 2) every 8 weeks after 5 initial monthly doses with pro re nata dosing starting at week 56 (Q8W) or 3) received sham injections.3 Eyes treated with aflibercept Q16W and Q8W achieved a 2-step or greater improvement in their DRSS score at 24 weeks and 52 weeks (P < 0.001 for both) (Figure 5).3 Eyes treated with aflibercept had a significantly lower risk of VTCs (Figure 6) and/or CI-DME through week 100 (18.7% Q8W and 16.3% Q16W vs 50.4% sham; P < 0.001 for both).3
Figure 5. Anti-VEGF therapy improved the DRSS level ≥2 steps in moderately severe to severe NPDR in the PANORAMA study.3
Figure 6. Anti-VEGF reduced the risk of VTCs in moderately severe to severe NPDR in the PANORAMA study.3
Protocol W and PANORAMA Takeaways
Patients who received anti-VEGF therapy in the Protocol W and PANORAMA trials did not have DME. Traditionally, ophthalmologists have not intervened with therapy in patients without DME. Rather, they have observed and carefully monitored the retinopathy in these patients and counseled them on good control of blood glucose and blood pressure. A takeaway from the Protocol W and PANORAMA data is to initiate conversations earlier on the option of therapy for advanced retinopathy without DME. Imaging findings may be used to inform patients and to guide conversations and treatment recommendations. Patients with advanced retinopathy should be watched closely by repeating ultra-widefield imaging and/or angiography often; thus, if signs of progression appear, anti-VEGF injections may be initiated as early as possible.
Case Study 2
An asymptomatic 35-year-old man presented for a routine eye examination. He had a history of type 2 diabetes for 8 years with an unknown HbA1c. Four years ago, he was diagnosed with severe NPDR based upon intraretinal microvascular abnormalities (IRMA) OD and scheduled for a 4-month follow-up visit (Figure 7); however, he was lost to follow-up. Current fundus photography showed high-risk PDR with neovascularization and a subhyaloid hemorrhage OD (Figure 8). Over 4 years, this patient migrated to a higher risk category for blindness owing to a lack of treatment.
Figure 7. Patient’s ultra-widefield imaging from 4 years prior showing severe NPDR pathology OD.
Figure 8. Patient’s current ultra-widefield imaging showing high-risk PDR pathology OD.
Clinical Implications of Protocol W and PANORAMA
DR is an indicator of systemic disease, and the evidence in Protocol W and PANORAMA gives a starting point to discuss initiating treatment earlier to potentially prevent VTCs. The sham groups in the studies portend probable outcomes in the real world for patients who are nonadherent to follow-up visits and anti-VEGF injections. For patients who are adherent to therapy, Protocol W data suggested that anatomic outcomes significantly improved in the anti-VEGF treated groups compared with the sham group, but the visual outcomes were similar (Figure 4). However, this comparison was conducted over only 2 years of data and occurred within a clinical trial population. Real-world patients have difficulty fully adhering to their visits for frequent injections, whether due to a pandemic or life stressors. Yet, to modify the disease course and reach a better outcome overall, frequent injections are necessary.
Save Sight Key Takeaways
We continue to discover ways to alter and manage treatment options earlier in the disease course of DR. Advanced diagnostic tools, such as ultra-widefield FA, are essential in diagnosing disease by readily detecting pathology, including retinal nonperfusion. Recent data indicate that patients with moderate NPDR may potentially begin anti-VEGF therapy before the disease reaches a more severe stage, which is earlier than the traditional approach to treatment. Therefore, the importance of appropriate referrals to closely monitor DR for signs of progression cannot be overemphasized. These referrals will allow for the timely initiation of vision-saving treatment.
- Wykoff CC, Khurana RN, Nguyen QD, et al. Risk of blindness among patients with diabetes and newly diagnosed diabetic retinopathy. Diabetes Care. 2021;44(3):748-756.
- Maturi RK, Glassman AR, Josic K, et al. Effect of intravitreous anti-vascular endothelial growth factor vs sham treatment for prevention of vision-threatening complications of diabetic retinopathy: the Protocol W randomized clinical trial. JAMA Ophthalmol. 2021;139(7):701-712.
- Brown DM, Wykoff CC, Boyer D, et al. Evaluation of intravitreal aflibercept for the treatment of severe nonproliferative diabetic retinopathy: results from the PANORAMA randomized clinical trial. JAMA Ophthalmol. 2021;139(9):946-955.
In accordance with the ACCME Standards for Integrity and Independence, Global Learning Collaborative (GLC) requires that individuals in a position to control the content of an educational activity disclose all relevant financial relationships with any ineligible company. GLC mitigates all conflicts of interest to ensure independence, objectivity, balance, and scientific rigor in all its educational programs.
Avni P. Finn, MD, MBA
Vanderbilt University Medical Center
Consulting Fees: Allergan, Genentech
Jayanth Sridhar, MD
Associate Professor of Clinical Ophthalmology
Associate Residency Program Director
Bascom Palmer Eye Institute, University of Miami
No relevant relationships reported.
- Emily Chew, MD, has nothing to disclose.
- Cindy Davidson has nothing to disclose.
- Ann Early has nothing to disclose.
- Amanda Hilferty has nothing to disclose.
- Robert Schneider, MSW, has nothing to disclose.
- Stephanie Wenick, MPhil has nothing to disclose.
After participating in this educational activity, participants should be better able to:
- Refer patients with suspected moderate to severe nonproliferative diabetic retinopathy (NPDR) to retina specialists for prompt evaluation and preventive care
- Explore emerging data for preventing progression and vision-threatening complications of diabetic retinopathy
This activity is designed to meet the educational needs of optometrists, eye health nurses, primary care physicians, nurse practitioners, physician assistants, and nurses.
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